Current estimates from the American Cancer Society indicate that over 70,000 new cases of urothelial carcinoma (UC) are diagnosed annually in the US alone, and over 14,000 will die from the disease. While many patients' tumors recur in the urinary tract only, this relapsing non-invasive disease is usually not life-threatening. In contrast, other patients develop invasive and/or metastatic disease, the lethal phenotype of UC. While our understanding of the molecular changes in UC has rapidly evolved over the last few decades, the therapeutic arsenal has not. First-line treatment for advanced disease remains platinum-based combination chemotherapy, and no FDA-approved second-line treatment exists. Attempts to improve current therapies have focused on cytotoxic chemotherapy dose intensity and combination doublet and triplet regimens, none of which have led to substantial improvements in survival. Metastatic UC remains incurable in the vast majority of patients, with a median survival of approximately 8 months without treatment, and 14 months with treatment. Unlike treatment of other solid tumors, targeted therapies thus far have failed to advance the standard of care for UC. Furthermore, there is no clear molecular understanding of what defines the lethal phenotype of UC. Thus, there is an urgent need for new biomarkers and treatment approaches.